Hepatic fibrosis

Jiao, Jingjing; Friedman, Scott L.; Aloman, Costica

doi:10.1097/mog.0b013e3283279668

Cited by 206 publications

(150 citation statements)

References 57 publications

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“…This correlates directly with the histologic features of human SOS where a significant proportion of patients develop centrilobular perisinusoidal and vein occlusive fibrosis (1,2,4,15,40). In the animal model deposition of collagen in the sinusoids also occurs, albeit as late event (18), when activated, HSC acquire a myofibroblastic phenotype and are essential actors in hepatic fibrosis (41) as underlined by the diffuse perisinusoidal aSM actin expression (1).…”

Section: Discussionmentioning

confidence: 91%

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Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

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Section: Discussionmentioning

confidence: 91%

“…Our molecular observation could partially explain this clinical observation. VEGF blockade by bevacizumab could lead to downregulation of MMP expression by SEC (41,46), and thus attenuate sinusoidal lesions. VEGF-C mRNA was increased in SOS whereas VEGF-A remained at the same level as in controls.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Rubbia‐Brandt

Tauzin

Brézault

et al. 2011

Molecular Cancer Therapeutics

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“…Previous in vitro experiments of Oben et al 10 had shown that HSCs that are crucial for sinusoidal fibrosis producing most of the interstitial ECM 24 express a-and b-adrenoceptors. Additionally, HSCs are able to biosynthesize catecholamines because of their subset of metabolizing enzymes.…”

Section: Discussionmentioning

confidence: 99%

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Strack

Schulte

Varnholt

et al. 2011

Laboratory Investigation

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Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra-and extrahepatic bile ducts. Until now, no effective medical therapy exists. To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the b-adrenoceptors, we used the Mdr2 À/À mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2 À/À mice untreated or treated with the b-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for a-smooth muscle actin (a-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-b, TNF-a, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2 À/À mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2 À/À mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the b-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-a, TGF-b, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis. Therefore, the blockade of b-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

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“…There is overwhelming evidence that activated hepatic stellate cells (HSCs) are the major producers of the fibrotic neomatrix, although additional cellular sources, such as portal myofibroblasts, bone marrow-derived cells and epithelial-tomesenchymal transition (EMT), have been reported (Forbes and Parola, 2011;Jiao et al, 2009). Upon liver injury, quiescent HSCs undergo phenotypic transition into myofibroblast-like cells, which is invariably associated with loss of cytoplasmic vitamin A-containing lipid droplets, positive staining for α-smooth muscle actin (α-SMA), and greatly increased synthesis of the ECM proteins (Friedman, 2008).…”

Section: Introductionmentioning

confidence: 99%

Retinol Binding Protein-Albumin Domain III Fusion Protein Deactivates Hepatic Stellate Cells

Park

Choi

Lee

et al. 2012

Molecules and Cells

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Liver fibrosis is characterized by accumulation of extracellular matrix, and activated hepatic stellate cells (HSCs) are the primary source of the fibrotic neomatrix and considered as therapeutic target cells. We previously showed that albumin in pancreatic stellate cells (PSCs), the key cell type for pancreatic fibrogenesis, is directly involved in the formation of vitamin A-containing lipid droplets, inhibiting PSC activation. In this study, we evaluated the anti-fibrotic activity of both albumin and retinol binding protein-albumin domain III fusion protein (R-III), designed for stellate cell-targeted delivery of albumin III, in rat primary HSCs and investigated the underlying mechanism. Forced expression of albumin or R-III in HSCs after passage 2 (activated HSCs) induced lipid droplet formation and deactivated HSCs, whereas point mutations in high-affinity fatty acid binding sites of albumin domain III abolished their activities. Exogenous R-III, but not albumin, was successfully internalized into and deactivated HSC-P2. When HSCs at day 3 after plating (pre-activated HSCs) were cultured in the presence of purified R-III, spontaneous activation of HSCs was inhibited even after passage 2, suggestive of a potential for preventive effect. Furthermore, treatment of HSCs-P2 with R-III led to a significant reduction in both cytoplasmic levels of all-trans retinoic acid and the subsequent retinoic acid signaling. Therefore, our data suggest that albumin deactivates HSCs with reduced retinoic acid levels and that R-III may have therapeutic and preventive potentials on liver fibrosis.

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Hepatic fibrosis

Cited by 206 publications

References 57 publications

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Retinol Binding Protein-Albumin Domain III Fusion Protein Deactivates Hepatic Stellate Cells

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